A systems biology understanding of the synergistic effects of arsenic sulfide and Imatinib in BCR/ABL-associated leukemia
A systems biology understanding of the synergistic effects of arsenic sulfide and Imatinib in BCR/ABL-associated leukemia
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DOI：
10.1073/pnas.0813142106
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发表时间：
2009-03-03
影响因子：
11.1
通讯作者：
Chen, Zhu
中科院分区：
文献类型：
--
作者：
Zhang, Qun-Ye;Mao, Jian-Hua;Chen, Zhu
在这项研究中，我们表明，伊马替尼（IM）和硫化砷[As 4S 4（AS）]的联合使用发挥更深刻的治疗作用，在BCR/ABL阳性小鼠模型的慢性粒细胞白血病（CML）比任何一种药物作为单一的代理。系统分析AS和/或IM处理后K562细胞中蛋白质组、磷酸化蛋白质组和转录组的动态变化，以解决这种协同作用的机制。我们的数据表明，AS促进未折叠蛋白反应（UPR）和泛素化途径的活动，这可能是该化合物药理作用的生化基础。在该CML模型中，AS通过关键赖氨酸残基的泛素化靶向BCR/ABL，导致其蛋白酶体降解，而IM抑制PI 3 K/AKT/mTOR通路。两种药物的组合协同阻滞细胞周期，降低BCR/ABL的活性，并通过对转录和蛋白质水平的复杂修饰导致内源性和外源性凋亡途径的激活。因此，这些结果表明IM/AS联合治疗对人CML的潜在临床益处。
In this study, we show that combined use of Imatinib (IM) and arsenic sulfide [As4S4 (AS)] exerts more profound therapeutic effects in a BCR/ABL-positive mouse model of chronic myeloid leukemia (CML) than either drug as a single agent. A systematic analysis of dynamic changes of the proteome, phosphoproteome, and transcriptome in K562 cells after AS and/or IM treatment was performed to address the mechanisms underlying this synergy. Our data indicate that AS promotes the activities of the unfolded protein reaction (UPR) and ubiquitination pathway, which could form the biochemical basis for the pharmacological effects of this compound. In this CML model, AS targets BCR/ABL through the ubiquitination of key lysine residues, leading to its proteasomal degradation, whereas IM inhibits the PI3K/AKT/mTOR pathway. Combination of the 2 agents synergistically arrests the cell cycle, decreases activity of BCR/ABL, and leads to activation of intrinsic and extrinsic apoptosis pathways through complex modifications to both transcription and protein levels. Thus, these results suggest potential clinical benefits of IM/AS combination therapy for human CML.